Abnormalities of cardiac rhythm are a major public health problem. Drugs suppress cardiac arrhythmias in some patients, yet exacerbate arrhythmias or even generate new ones - the phenomenon of proarrhythmia - in others. This variability is not confined to antiarrhythmic drugs alone: in fact, the risk of proarrhythmia related to excessive prolongation of the QT interval has been the single leading cause of drug withdrawal over the past decade. While rare monogenic arrhythmia syndromes have been recognized for decades, more recent work strongly supports the overall hypothesis tested here, that common DMA variants underlie not only variability in cardiac rhythm but also the response of normal and abnormal cardiac rhythms to drug exposure. In Specific Aim 1, we will identify coding and non-coding variants and haplotypes in genes that are candidate modulators of cardiac rhythm, and functionally characterize these in vitro; these studies will inform the refinement of our current multiplexed arrhythmia genotyping platforms. In Specific Aim 2, we propose a series of studies to define genomic contributors to variable QT responses to drug therapy. In Specific Aim 3, variability in drug response in atrial fibrillation, the commonest arrhythmia for which drug therapy is currently prescribed, will be evaluated; here, we include a focus on "non-traditional" signaling pathways, such as the renin-angiotensin system and inflammation, that contemporary electrophysiology increasingly implicates in this arrhythmia. The Specific Aims will be supported by scientific Core resources devoted to ascertainment, DMA banking, database management, epidemiology and statistics, polymorphism discovery, genotyping, and functional studies. Participation in the Network will enable the long-term vision of exploiting human genomic information for more rationale drug development and [unreadable] [unreadable]